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DYX1C1 is required for axonemal dynein assembly and ciliary motility

DYX1C1 is required for axonemal dynein assembly and ciliary motility
DYX1C1 is required for axonemal dynein assembly and ciliary motility
DYX1C1 has been associated with dyslexia and neuronal migration in the developing neocortex. Unexpectedly, we found that deleting exons 2–4 of Dyx1c1 in mice caused a phenotype resembling primary ciliary dyskinesia (PCD), a disorder characterized by chronic airway disease, laterality defects and male infertility. This phenotype was confirmed independently in mice with a Dyx1c1 c.T2A start-codon mutation recovered from an N-ethyl-N-nitrosourea (ENU) mutagenesis screen. Morpholinos targeting dyx1c1 in zebrafish also caused laterality and ciliary motility defects. In humans, we identified recessive loss-of-function DYX1C1 mutations in 12 individuals with PCD. Ultrastructural and immunofluorescence analyses of DYX1C1-mutant motile cilia in mice and humans showed disruptions of outer and inner dynein arms (ODAs and IDAs, respectively). DYX1C1 localizes to the cytoplasm of respiratory epithelial cells, its interactome is enriched for molecular chaperones, and it interacts with the cytoplasmic ODA and IDA assembly factor DNAAF2 (KTU). Thus, we propose that DYX1C1 is a newly identified dynein axonemal assembly factor (DNAAF4).
1061-4036
995-1003
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Slagle, Christopher E.
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Francis, Richard
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Köhler, Gabriele
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Griese, Matthias
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Chen, Serafine
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Lucas, Jane S
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Onoufriadis, Alexandros
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Plagnol, Vincent
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Lo, Cecilia W.
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Mitchison, Hannah M.
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Knowles, Michael R.
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Burdine, Rebecca D.
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LoTurco, Joseph J.
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Omran, Heymut
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Tarkar, Aarti
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Loges, Niki T.
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Slagle, Christopher E.
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Francis, Richard
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Shook, Brett
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Cantino, Marie
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Schwartz, Daniel
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Jahnke, Charlotte
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Olbrich, Heike
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Hjeij, Rim
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Griese, Matthias
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Li, You
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Mans, Dorus A.
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Carson, Johnny L.
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Leigh, Margaret W.
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Wolf, Whitney E.
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Chen, Serafine
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Lucas, Jane S
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Onoufriadis, Alexandros
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Plagnol, Vincent
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Schmidts, Miriam
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Boldt, Karsten
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Roepman, Ronald
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Zariwala, Maimoona A.
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Lo, Cecilia W.
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Mitchison, Hannah M.
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Knowles, Michael R.
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Burdine, Rebecca D.
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LoTurco, Joseph J.
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Omran, Heymut
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Tarkar, Aarti, Loges, Niki T., Slagle, Christopher E., Francis, Richard, Dougherty, Gerard W., Tamayo, Joel V., Shook, Brett, Cantino, Marie, Schwartz, Daniel, Jahnke, Charlotte, Olbrich, Heike, Werner, Claudius, Raidt, Johanna, Pennekamp, Petra, Abouhamed, Marouan, Hjeij, Rim, Köhler, Gabriele, Griese, Matthias, Li, You, Lemke, Kristi, Klena, Nikolas, Liu, Xiaoqin, Gabriel, George, Tobita, Kimimasa, Jaspers, Martine, Morgan, Lucy C., Shapiro, Adam J., Letteboer, Stef J.F., Mans, Dorus A., Carson, Johnny L., Leigh, Margaret W., Wolf, Whitney E., Chen, Serafine, Lucas, Jane S, Onoufriadis, Alexandros, Plagnol, Vincent, Schmidts, Miriam, Boldt, Karsten, Roepman, Ronald, Zariwala, Maimoona A., Lo, Cecilia W., Mitchison, Hannah M., Knowles, Michael R., Burdine, Rebecca D., LoTurco, Joseph J. and Omran, Heymut (2013) DYX1C1 is required for axonemal dynein assembly and ciliary motility. Nature Genetics, 45 (9), 995-1003. (doi:10.1038/ng.2707). (PMID:23872636)

Record type: Article

Abstract

DYX1C1 has been associated with dyslexia and neuronal migration in the developing neocortex. Unexpectedly, we found that deleting exons 2–4 of Dyx1c1 in mice caused a phenotype resembling primary ciliary dyskinesia (PCD), a disorder characterized by chronic airway disease, laterality defects and male infertility. This phenotype was confirmed independently in mice with a Dyx1c1 c.T2A start-codon mutation recovered from an N-ethyl-N-nitrosourea (ENU) mutagenesis screen. Morpholinos targeting dyx1c1 in zebrafish also caused laterality and ciliary motility defects. In humans, we identified recessive loss-of-function DYX1C1 mutations in 12 individuals with PCD. Ultrastructural and immunofluorescence analyses of DYX1C1-mutant motile cilia in mice and humans showed disruptions of outer and inner dynein arms (ODAs and IDAs, respectively). DYX1C1 localizes to the cytoplasm of respiratory epithelial cells, its interactome is enriched for molecular chaperones, and it interacts with the cytoplasmic ODA and IDA assembly factor DNAAF2 (KTU). Thus, we propose that DYX1C1 is a newly identified dynein axonemal assembly factor (DNAAF4).

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e-pub ahead of print date: 21 July 2013
Published date: September 2013
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 354912
URI: http://eprints.soton.ac.uk/id/eprint/354912
ISSN: 1061-4036
PURE UUID: dab1c2eb-f06b-4fae-b08a-8fea21427425
ORCID for Jane S Lucas: ORCID iD orcid.org/0000-0001-8701-9975

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Date deposited: 07 Aug 2013 13:47
Last modified: 15 Mar 2024 03:12

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Contributors

Author: Aarti Tarkar
Author: Niki T. Loges
Author: Christopher E. Slagle
Author: Richard Francis
Author: Gerard W. Dougherty
Author: Joel V. Tamayo
Author: Brett Shook
Author: Marie Cantino
Author: Daniel Schwartz
Author: Charlotte Jahnke
Author: Heike Olbrich
Author: Claudius Werner
Author: Johanna Raidt
Author: Petra Pennekamp
Author: Marouan Abouhamed
Author: Rim Hjeij
Author: Gabriele Köhler
Author: Matthias Griese
Author: You Li
Author: Kristi Lemke
Author: Nikolas Klena
Author: Xiaoqin Liu
Author: George Gabriel
Author: Kimimasa Tobita
Author: Martine Jaspers
Author: Lucy C. Morgan
Author: Adam J. Shapiro
Author: Stef J.F. Letteboer
Author: Dorus A. Mans
Author: Johnny L. Carson
Author: Margaret W. Leigh
Author: Whitney E. Wolf
Author: Serafine Chen
Author: Jane S Lucas ORCID iD
Author: Alexandros Onoufriadis
Author: Vincent Plagnol
Author: Miriam Schmidts
Author: Karsten Boldt
Author: Ronald Roepman
Author: Maimoona A. Zariwala
Author: Cecilia W. Lo
Author: Hannah M. Mitchison
Author: Michael R. Knowles
Author: Rebecca D. Burdine
Author: Joseph J. LoTurco
Author: Heymut Omran

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